20.04.07 New-born Screening Flashcards
1
Q
Which committee is responsible for screening policies and programs in UK
A
UK National screening Committee
2
Q
How many newborns are screened every year
A
800,000
3
Q
What criteria did WHO develop to determine what disorders are suitable for screening
A
- Clinically and biochemically well-defined disorder
- Known incidence in populations relevant to the UK
- Disorder associated with significant morbidity or mortality
- Effective treatment available
- Period before onset where intervention improves outcome
- Ethical, safe, simple, robust screening test
- Cost effective
4
Q
What diseases are covered by UK newborn screening programme
A
- Pheylketonuria (PKU)
- Congenital hypothyroidism (CHT)
- Sickle cell anaemia
- CF
- Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
- Maple syrup disease (MSUD)
- Homocystinuria (pyridoxine unresponsive) (HCU)
- Glutaric Acidaemia type 1 (GA1)
- Isovaleric Acidaemia (IVA)
5
Q
Review of phenylketonuria (PKU)
A
- AR
- 1 in 10,000 in UK
- Mutations in PAH gene, phenylalanine hydroxylase enzyme
- Enzyme needed to metabolise phenylalanine (phe) to tyrosine (Tyr)
- Defects in enzyme cause toxic amounts of phenylalanine to build up
- If left untreated babies develop serious and irreversible mental disability
6
Q
How is phenylketonuria screened
A
- Tandem mass spectrometry is used to distinguish between PKU and other disorders
- No genetic testing involved. Avoids the detection of carriers. Treatments available make prenatal testing an ethical dilemma.
- Genetic testing can be useful as some mutations are amenable to treatment with BH4 supplements, reducing the need for strict dietary control.
7
Q
Review of congenital hypothyroidism (CHT)
A
- 1 in 3,000 babies born in UK
- Inborn error of metabolism where thyroid glands fail to produce thyroxine.
- Babies don’t grow properly, develop serious, permanent, physical and mental disability
- 10% cases are genetic
- Genetically heterogenous. Mainly AR, some ad
8
Q
How is congenital hypothyroidism screened
A
- Levels of thyroid stimulating hormone (TSH), also known as thyrotropin
- Treated with thyroxine tablets, allowing normal development
- Not all secondary hypothyroidism will be detected. Although they often have other health problems (jaundice, low blood sugar, small genitals), so often diagnosed easily
9
Q
Review of medium-chain acyl CoA dehydrogenase (MCADD)
A
- Affects 1 in 10,000 babies born in UK
- 1 in 52-83 carrier frequency. Likely a Northern European founder effect. Rare in other ethnicities.
- AR. Mutations in ACADM gene.
- Leads to a buildup of medium chain fatty acids, in particular octanoylcarnitine (C8)
- Body cannot efficiently use fats as part of glucose homeostasis. A problem in early infancy when glyconeolysis is not sufficient in periods of starvation.
10
Q
What is screened in medium-chain acyl CoA dehydrogenase
A
- Tandem mass spectrometry to measure C8 levels.
- Mutation screening for c.985A>G p.(Lys304Glu), present in 88% cases
- Functional MCAD protein contains 4 monomers that form a tetramer. Missense mutations cause tetramer to dissociate, reducing activity and affinity for substrates.
11
Q
Review sickle cell disease
A
- Affects 1 in 1,900 babies born in UK
- AR
- Red blood cells are sickle shaped, reducing flexibility. Unable to pass through narrow capillaries leading to vessel occlusion and ischaemia. Can lead to organ damage, stroke, infection, pain and death.
- Haemoglobin A makes up 95% of haemoglobin. Has 2 alpha and 2 beta chains.
- SCD caused by mutation in beta globin chain, HBB c.20A>T p.(Glu6Val).
- More common in people originating from tropical regions where malaria is common. A single sickle cell gene confers an advantage.
12
Q
Testing for sickle cell disease
A
- High performance liquid chromatography (HPLC), isoelectric focusing (IEF), capillary electrophoresis.
- HPLC: measures elution time of various haemoglobin proteins in various buffer solutions. Can detect carriers and affecteds
- IEF: separates proteins by charge and molecular weight (gel with pH gradient).
13
Q
Review of CF
A
- Affects 1 in 2,500 babies
- Carrier rate is 1 in 25 in UK
- AR
- Disorder when digestive system and lungs get clogged with thick sticky mucus. Poor weight gain and frequent chest infections.
14
Q
Testing for CF
A
- Looks for raised levels of immunoreactive trypsinogen (IRT)
- Fluoroimmunometric assay. 2 monoclonal antibodies (1 bound to plate and one europium labelled) are directed against 2 antigens on IRT.
- Genetics: common 4 mutation screen. F508del, Gly551Asp, Gly542X, c.489+1G>T
15
Q
CF result interpretation
A
- 2 mutations CF suspected. Immediate referral to CF specialist
- 1 CFTR mutation, IRT on second blood spot. If elevated then CF suspected, if low then probably CF carrier
- No mutation detected. If first IRT was above 99.99th centile then second blood spot taken at 21 days. If below 99.99th centile then CF not suspected.
- Poor predictive value of IRT alone, so genetic testing needed.
16
Q
Review of maple syrup disease
A
- Incidence= 1 in 200,000 live births. Higher in certain ethnic groups
- AR due to mutations in branched chain 2-keto acid dehydrogenase (BCKAD) complex.
- Defects lead to accumulation of amino acids leucine, isoleucine, allo-leucine and valine. Cause toxicity in brain and skeletal muscle.
- Genetic heterogeneity due to mutations in genes encoding subunits of BCKAD (BCKDHA, BCKDHB, DBT, DLD)
- Vomiting, lethargy, progressive neurological deterioration, maple syrup odour to urine
17
Q
Screening of Maple syrup disease
A
- Tandem mass spectrometry (ms/ms)
- Quantifies the levels of leucine, isoleucine, allo-isoleucine and valine. Although cannot distinguish between them as they all have the same mass. Combined peak for all 4 analytes.
- Elevated levels of “leucines”. Then followed up with measurement of allo-isoleucine in blood spots.
18
Q
Review of homocystinuria
A
- Incidence is 1 in 100,000 live births. Higher in certain ethnic groups
- AR due to mutations in CBS gene. Cystathionine beta-synthase.
- Defects lead to catabolism of methionine, leading to toxic accumulation of homocysteine.
- Learning difficulties, skeletal abnormalities, myopia, thrombotic episodes.
- Treatment is low methionine diet. 50% are responsive to vitamin B6 (pyridoxine)
19
Q
Homocystinuria screening
A
-Tandem mass spectrometry (MS/MS) to measure levels of methionine (raised) and total homocysteine in blood spots.
20
Q
Review of glutaric acidaemia type 1 (GA1)
A
- Incidence is 1 in 100,000 live births in Europe.
- AR, due to mutations in glutaryl-CoA-dehydrogenase (GCDH) gene
- Defective catabolism of glutaryl-A, an intermediate in break down of amino acids lysine, hydroxylysine and tryptophan. Leads to a toxic accumulation of glutaric acid.
- Macrocephaly, encephalopathic crisis, GI infection or pneumonia.
- R402W most prevalent mutation in Caucasians
- Treatment is low protein, lysine-restricted diet. Supplementation of carnitine. Rapid treatment of ilness to prevent crises.
21
Q
Glutaric acidaemia type 1 testing
A
- Tandem Mass spectrometry (MS/MS)
- Quantifies glutarylcarnitine (C5DC) in blood spots
- Won’t detect GA1 low excretors
22
Q
Review of isovaleric acidaemia (IVA)
A
- Incidence 1 in 100,000
- AR, mutations in IVD gene.
- Deficiency in mitochondrial enzyme isovaleryl-CoA-dehydrogenase
- Defective catabolism of the amino acid leucine, with toxic accumulation of isovaleric acid and its glycine and carnitine derivatives.
- Metabolic crisis, vomiting, lethargy, progressing to coma, failure to thrive, dev delay.
- Treatment: low protein diet. Glycine and L-carnitine can be administered to help clear excess isovaleric acid from body.
23
Q
Isovaleri acidaemia testing
A
- MS/MS. Detects elevated C5 (isovalerylcarnitine) in blood spots
- Urine organic acid analysis (differentiate between IVA and GA2)
